U.S. patent number 6,890,553 [Application Number 09/612,357] was granted by the patent office on 2005-05-10 for exothermic topical delivery device.
This patent grant is currently assigned to Johnson & Johnson Consumer Companies, Inc.. Invention is credited to Ralph W. Oakeson, Ying Sun, Jonas C. T. Wang, Stephen J. Wisniewski.
United States Patent |
6,890,553 |
Sun , et al. |
May 10, 2005 |
Exothermic topical delivery device
Abstract
The present invention relates to an exothermic device for
topically delivering an active agent comprising a liquid reservoir
comprising water, a heating element comprising an oxidizable
material, an oxygen-permeable outer-layer, an active agent, and a
water-impermeable layer, wherein upon the rupturing of the liquid
reservoir, the water contacts the heating element and the oxygen to
create and exothermic reaction.
Inventors: |
Sun; Ying (Somerville, NJ),
Oakeson; Ralph W. (Racine, WI), Wisniewski; Stephen J.
(Doylestown, PA), Wang; Jonas C. T. (West Windsor, NJ) |
Assignee: |
Johnson & Johnson Consumer
Companies, Inc. (Skillman, NJ)
|
Family
ID: |
34555167 |
Appl.
No.: |
09/612,357 |
Filed: |
July 7, 2000 |
Current U.S.
Class: |
424/449; 424/400;
424/443; 424/447; 424/448; 602/41; 602/46 |
Current CPC
Class: |
A61F
7/034 (20130101); A61B 2018/064 (20130101); A61F
2007/0001 (20130101); A61F 2007/0276 (20130101); A61F
2013/00902 (20130101) |
Current International
Class: |
A61B
18/04 (20060101); A61F 13/00 (20060101); A61B
18/06 (20060101); A61K 009/70 () |
Field of
Search: |
;424/449,448,447,443,402,400 ;602/41,46 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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Other References
Sun, Y. Skin Absorption Enhancement by Physical Means: Heat,
Ultrasound, and Electricity. Transdermal and Topical Drug Delivery
Systems. (1997) 327-355. .
Buyuktimkin N., Buyuktimkin S. Chemical Means of Transdermal Drug
Permeation Enhancement. Transdermal and Topical Drug Delivery
Systems. (1997) 357-475. .
Sun Y., Liu J.C., Xue H. Important Parameters Affecting
Iontophoretic Transdermal Delivery of Insulin. Proceed. Intern.
Symp. Control. Rel. Bioact. Mater., 17, Controlled Release Society,
Inc. (1990) 202-203. .
Roberts M. Lai P., Cross S., Yoshida N. Solute Structure as a
Determinant of Iontophoretic Transport. Mechanisms of Transdermal
Drug Delivery. (1997) 291-349. .
PCT Search Report Dated Oct. 25, 2000 of International Application
No. PCT/US 00/18650..
|
Primary Examiner: Page; Thurman K.
Assistant Examiner: George; Konata M.
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATION
This application claims the benefit of provisional application Ser.
No.: 60/142,757 filed on Jul. 8, 1999.
Claims
What is claimed is:
1. An exothermic device for topically delivering an active agent,
said device comprising: (a) a plurality of liquid reservoirs,
wherein said reservoirs are capsules comprising water; (b) a
heating element, said heating element comprising an oxidizable
material and where said heating element is in communication with
said liquid reservoir; (c) an oxygen-permeable outer-layer, wherein
said oxygen-permeable layer is in communication with said heating
element, permits oxygen from the environment to contact said
heating clement, and substantially inhibits the permeation of water
from the heating element into the environment; (d) an active agent;
and (e) a water-impermeable layer, wherein said water-impermeable
layer separates said heating element and said active agent; wherein
upon the rupturing of said liquid reservoir, said water contacts
said heating element and said oxygen to create an exothermic
reaction.
2. A device of claim 1, wherein said liquid reservoir is contained
between said oxygen-permeable layer and said water-impermeable
layer.
3. A device of claim 1, wherein said device further comprises an
adhesive layer, said adhesive layer comprising an adhesive for
affixing said device to the skin of the user.
4. A device of claim 3, wherein said device further comprises a
removable liner affixed to said adhesive layer.
5. A devise of claim 3, wherein said adhesive layer comprises said
active agent.
6. A device of claim 1, wherein said liquid reservoir further
comprises a salt, said salt selected from the group consisting of
NaCl, KCl, CaCl.sub.2, FeCl.sub.3, FeCl.sub.2, MgCl.sub.2,
AlCl.sub.3, Na.sub.2 SO.sub.4, K.sub.2 SO.sub.4,
Fe(SO.sub.4).sub.3, FeSO.sub.4, or MgSO.sub.4.
7. A device of claim 1, wherein said heating element further
comprises a salt, said salt selected from the group consisting of
NaCl, KCl, CaCl.sub.2, FeC1.sub.3, FeCl.sub.2, MgCl.sub.2,
AlCl.sub.3, Na.sub.2 SO.sub.4, K.sub.2 SO.sub.4,
Fe(SO.sub.4).sub.3, FeSO.sub.4, or MgSO.sub.4.
8. A device of claim 1, wherein said oxidizable material comprises
carbon and metal powder, said metal powder selected form the group
consisting of iron, aluminum, magnesium, zinc, and a mixture
thereof.
9. A device of claim 1, wherein said oxidizable material comprises
carbon and an inorganic powder, said inorganic powder selected from
the group consisting of ferrosoferric oxide, plumboblumbic oxide,
trimanganese tetroxide, black copper oxide and manganese
dioxide.
10. A device of claim 1, wherein said heating element is contained
within a water-permeable membrane.
11. A device of claim 1, wherein said heating clement further
comprises a polymer.
12. A device of claim 1, wherein said active agent is for the
treatment of acne.
13. A device of claim 1, wherein said oxygen-permeable layer is an
open-oell foam.
14. A device of claim 1, wherein said device further comprises a
removable oxygen-impermeable cover sheet affixed to said
oxygen-permeable layer.
15. A device of claim 1, wherein said exothermic reaction is
between about 40.degree. C. and 42.degree. C.
16. A method of topically delivering an active agent to a mammal,
said method comprising attaching the device of claim 1 to a barrier
membrane of said mammal.
17. A method of claim 16, wherein said mammal is a human.
18. A method of claim 17, wherein said device is attached to the
skin of said human.
19. A method of claim 17, wherein said device is attached a mucosal
layer of said human.
Description
FIELD OF THE INVENTION
The present invention relates to a delivery device comprising a
heating element and the use thereof for enhanced topical and
transdermal delivery of active agents.
BACKGROUND OF THE INVENTION
To Topical dosage forms have been widely prescribed for decades in
the treatment of systemic diseases and local conditions such as
those involved with the skin and underlying tissues. Certain drugs
are relatively easy to be delivered via the transdermal or
transmucosal route because they can easily permeate through the
skin or mucosal membrane at a high potency. Permeation of the drug
across the skin or mucosal membrane from a transdermal patch or a
mucosal patch is a result of the chemical potential gradient across
the skin or mucosal membrane. Examples of these drugs include
nitroglycerin, scopolamine, nicotine, hydrocortisone,
betamethasone, benzocaine, and lidocaine.
Most drugs and biological active ingredients, however, cannot
readily penetrate through the skin or mucosal membrane. Therefore,
to increase skin permeation of these drugs, various chemical and
physical permeation enhancing methods have been employed. Chemical
permeation enhancing agents may be applied typically to increase
transdermal delivery of drugs. Generally, chemical permeation
enhancing agents are cost effective and safe. An extensive review
of chemical penetration enhancing agents is reported in Buyuktimkin
et al., "Chemical Means of Transdermal Drug Permeation
Enhancement", Transdermal and Topical Drug Delivery Systems,
Interpharm Press, Inc., 1997, pages 357-475. One major disadvantage
associated with chemical penetration enhancers is potential skin
irritation.
Physical penetration enhancing methods can also be used to improve
transdermal drug delivery. The energy forms employed for this
purpose include electricity (e.g., iontophoresis), ultrasound
(e.g., phonophoresis) and thermal energy (e.g., heat-assisted
delivery), which are reviewed by Sun, "Skin Absorption Enhancement
by Physical Means: Heat, Ultrasound, and Electricity", Transdennal
and Topical Drug Delivery Systems, Interpharm Press, Inc., 1997,
pages 327-355.
U.S. Pat. No. 4,898,592 relates to a device for the application of
heated transdermally absorbable active substances that includes a
carrier impregnated with the transdermally absorbable active
substance and a support. The support is a laminate made up of one
or more polymeric layers and optionally includes a heat conductive
element. This heat conductive element is used for distribution of
the patient's body heat such that absorption of the active
substance is enhanced. This device, however, has no heat-generating
element or function. The use of only a heat conductive element to
distribute body heat, however, is not an efficient or reliable
method of enhancing transdermal absorption by heating since the
amount of body heat given off by a patient can vary depending on
the ambient air temperature and the physical conditions of the
patient.
U.S. Pat. No. 4,747,841 discloses a method and apparatus for
"moxibustion" using a heat-generating element to heat and vaporize
"moxall " for treatment of a patient's skin without leaving burn
scars. The objective of this method and apparatus, however, is to
achieve heat stimulation of the body and not to increase skin
permeability.
U.S. Pat. No. 4,230,105 discloses a bandage with a drug and a
heat-generating substance, preferably intermixed, to enhance the
rate of absorption of the drug by the user's skin. Separate drug
and heat-generating generation substance layers are also disclosed.
water must be applied to the bandage to activate the heating
substance to release solvation heat. Because the exothermal
reaction during the hydration of the electrolytes disclosed in this
patent only produces a transient low level of heat, it cannot be
effectively used as a penetration enhancing method over a long
period of time (e.g., for up to one day). Further, the speed of the
hydration process is rather difficult to control.
U.S. Pat. No. 4,685,911 discloses a skin patch including a drug
component and an optional heating element for melting the
drug-containing formulation if the user's body temperature is
inadequate to do so. The heating element is not substantially
co-extensive with the drug reservoir, the latter being quite thick
and, thus, not susceptible to even and rapid onset of heating.
There is also no description on how to control the exothermic
reaction to have prolonged and even heating.
U.S. Pat. No. 4,963,360 describes an exothermic device having a
carrier layer, which comprises a medicinal component, and an
exothermic layer, which develops heat when exposed to the air to
enhance absorption of the medicinal component through the skin. The
exothermic layer comprises a mixture of iron powder, carbon powder,
salts (i.e., sodium chloride and aluminum chloride), and water.
There is a base sheet to separate the exothermic layer from the
medicinal layer in two separate chambers, and an air-permeable film
that covers the exothermic layer.
U.S. Pat. No. 5,658,583 describes a heat-generating generation
apparatus for improved dermal permeation of pharmaceuticals. The
apparatus includes a thin drug formulation reservoir and a
heat-generating chamber separated by a non-permeable wall. The drug
formulation reservoir houses a predetermined amount of a
formulation containing pharmaceutical agents. The
heat-generating/temperature-regulating chamber includes a
heat-generating medium consisting of carbon, iron, water and/or
salt which is activated upon contact with oxygen in the air. The
structure of the apparatus also includes a cover that is not
permeable to air, but is perforated with holes to regulate the
contact between the heat-generating medium and air, thereby,
controlling the heating temperature.
U.S. Pat. No. 5,662,624 describes a heat dressing for treatment of
skin areas comprising a heat generating unit and a liquid-absorbing
adhesive layer that, prior to use, is coated with a release layer.
The adhesive layer is preferably made of a hydro-colloidal material
and may optionally contain one or more medicaments or may be coated
with alginate fiber mats. The heat-generating unit generates heat
preferably by means of galvanic or chemical energy, and the heat
dressing may further comprise elements for controlling the heat
development and/or the surface temperature. Such elements include a
cover sheet for the heat-generating unit that is perforated for air
passage, is covered by a heat-reflecting foil, or is a polymeric
foam to better retain the heat.
The present invention relates to an exothermic delivery device for
administration of active agents through a barrier membrane (e.g.,
the skin, mucosal membrane, or nails of a human). The advantages of
the present device include: better-controlled heatgeneration
process, and consequently, an improved delivery profile of the
active agents; an easier control on the product stability during
storage; and simple manufacturing process for the device.
SUMMARY OF THE INVENTION
In one aspect, the invention features An exothermic device for
topically delivering an active agent, the device comprising: (a) a
liquid reservoir, the reservoir comprising water; (b) a heating
element, the heating element comprising an oxidizable material and
where the heating element is in communication with the liquid
reservoir; (c) an oxygen-permeable outer-layer, wherein the
oxygen-permeable layer is in communication with the heating
element, permits oxygen from the environment to contact the heating
element, and substantially inhibits the permeation of water from
the heating element into the environment; (d) an active agent; and
(e) a water-impermeable layer, wherein the water-impermeable layer
separates the heating element and the active agent; wherein upon
the rupturing of the liquid reservoir, the water contacts the
hating element and the oxygen to create and exothermic
reaction.
In another aspect, the invention features a method of topically
delivering an active agent to a mammal (e.g., a human), the method
comprising attaching the device of the present invention to a
barrier membrane (e.g., the skin, mucosal membrane, or nails) of
the mammal.
Other features and advantages of the present invention will be
apparent from the detailed description of the invention and from
the claims.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 is a cross-sectional view of an exothermic delivery device
for active agents showing one embodiment of the present
invention.
DETAILED DESCRIPTION OF THE INVENTION
It is believed that one skilled in the art can, based upon the
description herein, utilize the present invention to its fullest
extent. The following specific embodiments are to be construed as
merely illustrative, and not limitative of the remainder of the
disclosure in any way whatsoever.
Unless defined otherwise, all technical and scientific terms used
herein have the same meaning as commonly understood by one of
ordinary skill in the art to which the invention belongs. Also, all
publications, patent applications, patents, and other references
mentioned herein are incorporated by reference.
The present invention relates to a novel exothermic delivery device
of active agent(s) to barrier membranes, such as human skin,
muc/osal membrane (e.g., buccal membrane), and nails. The
exothermic delivery device of the present invention does not suffer
from many of the disadvantages of the existing apparatuses
previously described. For example, all of the prior devices
described above control the heat generation process by the mere
regulation of oxygen availability to the oxidation reaction in the
heat-generating medium, e.g., by covering the heat-generating
medium with a perforated membrane. The size and number of the
thermo-regulating holes on the permeable membrane, thus, determines
the amount of oxygen that reaches the oxidizable medium.
The disadvantages of such an approach include: (a) the requirement
for a strict control of a non-oxygen environment during the
manufacturing process since an extremely oxidizable mixture has to
be processed and packaged into each apparatus and (b) a strict
requirement on the type of packaging material for the finished
product since any leakage of atmospheric oxygen will not only
prematurely consume the heat-generating medium, but also stimulate
the decomposition of the drug substances as a result of the
elevated temperature.
The heating element of the present invention cannot react until
activated by the user as the device includes a separate liquid
reservoir containing the water requisite for the exothermic
reaction. As represented schematically in FIG. 1, the device 500
consists of active-agent unit 100 and a heating unit 200. The
active agent unit 100 comprises an active agent-containing layer
120 and a water-impermeable layer 130 separating the active
agent-containing layer 120 from the heating unit 200. The
water-impermeable layer 130 is impermeable to the active agent in
the active agent-containing layer 120 and any solid or liquid
material in the heating unit 200.
The water-impermeable layer may be made of flexible material
well-known in the art to be impermeable to water, e.g., polymers
such as polyethylene, polypropylene, polyvinyl acetate,
polyurethane, silicone rubber, and polyvinyl chloride.
The active agent-containing layer 120 comprises the active agent.
The active agent-containing layer may further comprise a carrier
compatible with the active agent, such as a hydrogel, an adhesive,
a semi-solid carrier such as a cream, lotion, ointment, or liquid
crystal. It may also comprise a solid supporting matrix (e.g., a
gauze or sponge-like foam materials). Active agents such as drugs
and nutrients and other biologically active agents are incorporated
into the carrier within the active agent-containing layer 120,
e.g., as dissolved molecules and ions, dispersed solid particles,
or liquid droplets.
As used herein, the term "active agents" refers drugs and nutrients
for local treatment or systemic treatment (e.g., a therapeutic or
cosmetic benefit). Typically these agent include, but are not
limited to, antihypertensive drugs (e.g., clonidine), analgesic
drugs (e.g. fentanyl, ibuprofen, benzocaine, and lidocaine), drugs
to treat coronary artery diseases (e.g., nitroglycerin, low
molecular weight heparin), drugs to assist wound healing (e.g.,
PDGF), antimicrobial agents, antipsoriatic agents,
anti-inflammatory agents, anticancer agents, endocrine and
metabolic medication (e.g., testosterone, estradiol), neurologic
medications, medication for cessation of chemical additions (e.g.,
nicotine), motion sickness (scopolamine), and protein and peptide
drugs. Most of these agents are known and may be used at
concentrations and for durations of time which have proved
effective against their respective disease states. These
therapeutic agents are described in "Goodman & Gilman's The
Pharmcological Basis of Therapeutics", 9.sup.th Edition by J. G.
Hardman,et al., (McGraw-Hill Companies, 1996).
Other active agents include those commonly used as for topical
treatment and in cosmetic treatment of skin tissues, such as
salicylic acid, benzoyl peroxide, resorcinol, resorcinol
monoacetate, and sulfur for acne, topical antibiotics for wounds,
topical antifungal drugs to treat fungal infections of the skin and
nails, and antipsoriatic drugs to treat psoriatic lesions of the
skin and psoriatic nails. Examples of antifungal drugs include but
are not limited to miconazole, econazole, ketoconazole,
itraconazole, fluconazole, voriconazole, clioquinol, bifoconazole,
terconazole, butoconazole, tioconazole, oxiconazole, sulconazole,
saperconazole, clotrimazole, undecylenic acid, haloprogin,
butenafine, tolnaftate, nystatin, ciclopirox olamine, terbinafine,
amorolfine, naftifine, elubiol, griseofulvin, and their
pharmaceutically acceptable salts. In one embodiement, the
antifungal drugs are an azole, an allylamine, or a mixture
thereof.
Examples of antibiotics (or antiseptics) include but are not
limited to mupirocin, neomycin sulfate bacitracin, polymyxin B,
1-ofloxacin, tetracyclines (chlortetracycline hydrochloride,
oxytetracycline hydrochloride and tetrachcycline hydrochoride),
clindamycin phsphate, gentamicin sulfate, benzalkonium chloride,
benzethonium chloride, hexylresorcinol, methylbenzethonium
chloride, phenol, quaternary ammonium compounds, triclocarbon,
triclosan, tea tree oil, and their pharmaceutically acceptable
salts.
Examples of antipsoriatic drugs include but are not limited to
corticosteroids (e.g., betamethasone dipropionate, betamethasone
valerate, clobetasol propionate, diflorasone diacetate, halobetasol
propionate, triamcinonide, dexamethasone, fluocinonide,
fluocinolone acetonide, halcinonide, triamcinolone acetate,
hydrocortisone, hydrocortisone venerate, hydrocortisone butyrate,
aclometasone dipropionte, flurandrenolide, mometasone furoate,
methylprednisolone acetate), methotrexate, cyclosporine,
calcipotriene and anthraline.
Additional examples of active agents include but are not limited to
minoxidil, minoxidil sulfate, retinoids, cysteine and acetyl
cysteine, methionine, glutathione, biotin, finasteride and ethocyn,
as well as pharmaceutically acceptable salts of these
compounds.
The active agents in the present invention may provide certain
benefits to the superficial tissues such as the skin, for example:
anti-aging, wrinkle removal, depigmentation (e.g., removal of "age
spot"), skin tone improvement. The exothermic device in the present
invention may be made into facial and body masks of various shape
and size to fit the contours of the anatomic locations. The
materials for the each layer of the multi-laminate device is
preferably pliant for this purpose. The examples of active agents
for aforementioned purposes include, but are not limited to: amino
acids, and their derivatives, biotin, vitamins, vitamin B complex:
thiamine, nicotinic acid, biotin, pantothenic acid, choline
riboflavin, vitamin B.sub.6, vitamin B.sub.12, pyridoxine,
inositol, carnitine; ascorbic acid, ascorbyl palmitate, vitamin A,
vitamin K, vitamin E, vitamin D, cysteine and N-acetyl cysteine,
herbal extracts, and their derivatives; soy extracts, calcium
pantothenate, calcium carbonate, and calcium gluconate. Examples of
retinoids include but not limited to retinol (Vitamin A alcohol),
retinal (Vitamin A aldehyde), retinyl acetate, etinyl palmitate,
retinoic cid, 9-cis-retinoic acid and 13-cis-retinoic acid.
Examples of flavonoids include but not limited to naringenin,
quercetin, catechins (e.g., epigallocatechin gallate), theaflavins,
robustaflavone, hinokiflavone, amentoflavone, agathisflavone,
volkensiflavone, morelloflavone, rhusflavanone, and
succedangeaflavanone.
The exothermic device 500 is suitable to be used deliver agents to
remove corn, callus, ingrown toe nails, and diseased nails from
infections. The active agents for such a treatment include, but are
not limited to, salicylic acid, urea, sodium sulfide, tannic acid,
salts of thioglycolic acid, cysteine and acetyl cysteine.
The exothermic device is also suitable to be used deliver agents
such as salicylic acid and benzoyl peroxide to treat acne.
The exothermic device is also suitable to be used deliver agents
such as retinoids and herbal and soy extracts to provide anti-aging
benefits including wrinkle and age-spot removal and improving skin
tone.
In another embodiment, the device does not comprise an active
agent-containing layer (e.g., it is used to help promote wound
healing as a bandage).
The device 500 comprises a pressure-sensitive adhesive 140 to
assist affixing the device 500 to the user's barrier membrane
(e.g., dermal or mucosal barrier membrane). The adhesive in the
adhesive layer may be a polymeric, pressure sensitive and
nonconductive and remains adherent even after prolonged exposure to
water. Typically, the adhesive has a broad working temperature
range. Suitable adhesive materials include, but are not limited to,
silicones, polyisobutylenes and derivatives thereof, acrylics,
natural rubbers, and combinations thereof. Suitable silicone
adhesives include, but are not limited to, Dow Corning.RTM. 355
available from Dow Corning of Midland, Mich; Dow Corning.RTM.
X7-2920; Dow Corning.RTM. X7-2960; GE 6574 available from General
Electric Company of Waterford, N.Y.; and silicone pressure
sensitive adhesives, such as those disclosed in U.S. Pat. Nos.
2,857,356, 4,039,707, 4,655,767, 4,898,920, 4,925,671, 5,147,916,
5,162,410, and 5,232,702. Suitable acrylic adhesives include, but
are not limited to, vinyl acetate-acrylate multipolymers,
including, such as Gelva.RTM. 7371, available from Monsanto Company
of St. Louis, Mo.; Gelva.RTM. 7881; Gelva.RTM. 2943; I-780 medical
grade adhesive available from Avery Dennison of Painesville, Ohio;
and acrylic pressure sensitive adhesives, such as those disclosed
in U.S. Pat. Nos. 4,994,267, 5,186,938, 5,573,778, 5,252,334, and
5,780,050.
A removable liner sheet 110 covers the active agent-containing
layer 120 and is attached to the adhesive layer 140. The selection
of the removable release-liner 110 is dependent on the type of the
adhesive in use, and is well known to a person skilled in the art.
The release-liner 110 is typically a polymer sheet or a paper
coated with a polymer, which have rather weak adhesion toward the
adhesive layer 140, therefore allowing itself being easily removed
prior to use without damaging the adhesive layer 140.
In addition to or in lieu of the adhesive 140, the apparatus 500
may be fastened to the body surface with an adhesive tape, an
elastic band, a band with a buckle (similar to a leather watch
band), or a Velcro band or the like.
Alternatively, the active agent unit 100 may be a transdermal patch
such as one of those transdermal active agent delivery devices
currently in the market. The examples include transdermal patches
of fentanyl (Duragesic.RTM. by Janssen Pharmaceutical),
nitroglycerin (Nitrodisc.RTM. by Roberts Pharmaceutical/G. D.,
Searle; Nitro-Dur.RTM. by Schering/Key Pharmaceutical; and
Transderm-Nitro.RTM. by Ciba-Geneva, and Minitran.RTM. by 3M
Riker), 17-.beta.-estradiol (Estraderm.RTM. by Ciba-Geneva),
clonidine (Catapres.RTM.-TTS by Boehringer Ingelheim), testosterone
(Testoderm.RTM. by Alza; and Androderm.RTM. by SmithKline Beecham),
scopolamine (Transderm-Scop.RTM. by Ciba-Geigy), nicotine
(Nicoderm.RTM. by Marion Merrell Dow; Habitrol.RTM. by Ciba-Geigy;
Nicotrol.RTM. by McNeil Consumer Products; and Prostep.RTM. by
Lerderle Lab).
Alternatively, the active agent unit 100 may be an iontophoretic,
electroporetic, or phonophoretic device such as one of those
devices well-known in the art, e.g., as disclosed in U.S. Pat. Nos.
4,927,408, 5,042,975, 5,224,927, 5,344,394, 5,667,491, 4,767,402,
and 5,636,632.
The heating unit 200 comprises a heat-generating layer 210 in which
heat-generating materials are immobilized, a liquid reservoir 220,
and an outer cover 250 under which the heat-generating layer 210
and liquid reservoir 220 are housed. The heat-generating layer 210
comprises a mixture of oxidizable materials (e.g., oxidizable metal
powder(s)) and carbon (e.g., activated carbon powder). Examples of
oxidizable metal powders include, are but not limited to, iron,
aluminum, magnesium, zinc, and a mixture thereof. Other oxidizing
material that can be used in the present invention to generate heat
include those described in U.S. Pat. No. 4,114,591 (e.g.,
ferrosoferric oxide, plumboblumbic oxide, trimanganese tetroxide,
black copper oxide and manganese dioxide in the form of fine
particle). The heat-generating layer 210 should be essentially free
of water or moisture prior to use (e.g., during storage).
The oxidation material may be immobilized by various means
including but not limited to a water-permeable permeable bag, mesh,
non-woven pad or other fabric materials, and binding agents (e.g.,
polymers) such as cellulose polymers, polyacrylic polymers,
polyurethanes, gelatins and gums. Examples of such polymers include
hydroxymethylcellulose, hydroxyethylcellulose,
hydroxypropylcellulose, cellulose actates, polyvinylvinylidone
(PVP), and copolymers of polyacrylic acid and polyacrylates
(Carboset.RTM., Carbopol.RTM. and Carbomerg.RTM.).
The liquid reservoir 220 contains (e.g., an easily rupturable
capsule made of a brittle material such as glass or plastic, or a
polymer such as polyethylene or polyacrylate) contains water and is
fabricated such that upon rupturing, it can either release all of
its contents at once to the heat-generating layer or slowly deliver
its contents to the heat-generating layer 210 in a pre-determined
and controlled manner (e.g., through sealed orifices in a flexible
capsule that easily open upon increased pressure). The rupturing
may be accomplished by applied pressure from the user. The liquid
reservoir 220 may additionally contain hydrogen peroxide.
The heat-generating layer or the liquid reservoir may additionally
contain electrolytes (e.g., salts that are placed in the liquid
reservoir 220 in the form of an aqueous solution). The
electrolytes/salts include, but are not limited to the salts of
sodium, potassium, lithium, calcium, iron, magnesium, and aluminum.
Examples of electrolytes include, but are not limited to, NaCl,
KCl, LiCl, CaCl.sub.2, FeCl.sub.3, FeCl.sub.2, MgCl.sub.2,
AlCl.sub.3, Na.sub.2 SO.sub.4, K.sub.2 SO.sub.4, Fe(
SO.sub.4).sub.3, FeSO.sub.4, or MgSO.sub.4.
The outer layer 250 is essentially water-impermeable with
controlled oxygen permeability. The outer layer 250 may be made of
highly oxygen-permeable polymer membranes such as silicone,
polyurethane, polyethylene, and polypropylene. It may be of a
microporous nature such as an open-cell foam, close-cell foam, or
open-cell foam with a water-impermeable polymer layer on one or
both side of the membrane. The extent of oxygen permeability of the
outer layer 250 is determined by the material it is made of, its
thickness, and its porosity. Optional, there may be a removable
cover sheet that is essential impermeable to oxygen and water
(e.g., moisture). The removable cover sheet must be partially or
fully removed to allow the device to heat. The removable cover
sheet may have an adhesive coated on one side in order to affix it
to the outer layer 250.
In order to use the device 500, the removable liner 110 is peeled
off, and the pressure-sensitive adhesive 140 and the active
agent-containing layer 120 of the device 500 is affixed to the a
barrier membrane (e.g., the skin) of the user. The heating unit 200
is activated by applying a slight pressure on the liquid reservoir
200 to rupture it. The water comes in contact with the
heat-generating layer 210 to start the exothermic reaction.
In the case where all of the liquid is release from the liquid
reservoir, heating is controlled by the amount of in-coming oxygen
through the outer layer 250, whose permeability to oxygen relies on
its intrinsic properties (e.g., membrane material, thickness, and
porosity). In one embodiment, to have a well-controlled heating
process, the removable cover sheet may be removed only partially to
limit the amount of oxygen entering the heating unit 200.
Alternatively, the removable cover sheet may be re-used used to
completely cover the outer layer to close the oxygen pathway and,
thus, stop the heating process. It may later be reopen to re-start
the heating process. In this way, the device in the present
invention can provide a pulsatile mode of enhanced active agent
delivery (e.g., alternating between baseline and heat-assisted
delivery).
In the case where the liquid reservoir contains rupturable
orifices, the control of the heat generation process may further be
determined by controlling the delivery of the water from the liquid
reservoir 220 to the heat-generating layer 210. The delivery rate
of the liquid can be controlled by the size and number of the
aforementioned orifices to provide an enhanced constant rate of
active agent delivery.
In another embodiment of the present invention, more than one
liquid reservoirs may be present in the device. Each liquid
reservoir may be individually ruptured at a predetermined time by
the user as needed. An enhanced delivery of active will follow each
rupturing of the liquid reservoir agents for a certain period of
time, thus, also resulting in a pulsatile delivery profile.
The target temperature range according to the present invention is
between about 38.degree. to about 50.degree. C. (e.g., between
about 40.degree. C. to 42.degree. C.). The heating period in the
present invention may vary dependent on the active agent being
delivered and may range from a few minutes to longer than a day. In
general, if the heating duration is short (e.g., less than 10
minutes), the operating temperature may be at the higher end of the
above temperature range. However, if the heating period is longer,
a lower operating temperature (e.g., less than 42.degree. C. is
preferred to avoid heat-related tissue injury.
It is understood that while the invention has been described in
conjunction with the detailed description thereof, that the
foregoing description is intended to illustrate and not limit the
scope of the invention, which is defined by the scope of the
appended claims. Other aspects, advantages, and modifications are
within the claims.
* * * * *